Molecular Cell
Volume 73, Issue 2, 17 January 2019, Pages 212-223.e7
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Article
Repression of Transcription at DNA Breaks Requires Cohesin throughout Interphase and Prevents Genome Instability

https://doi.org/10.1016/j.molcel.2018.11.001Get rights and content
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Highlights

  • Cohesin and PBAF repress gene transcription near DNA double-strand breaks (DSBs)

  • Transcriptional repression at DSBs requires cohesin and PBAF throughout interphase

  • Loss of DSB-induced gene repression leads to more large-scale genome alterations

Summary

Cohesin subunits are frequently mutated in cancer, but how they function as tumor suppressors is unknown. Cohesin mediates sister chromatid cohesion, but this is not always perturbed in cancer cells. Here, we identify a previously unknown role for cohesin. We find that cohesin is required to repress transcription at DNA double-strand breaks (DSBs). Notably, cohesin represses transcription at DSBs throughout interphase, indicating that this is distinct from its known role in mediating DNA repair through sister chromatid cohesion. We identified a cancer-associated SA2 mutation that supports sister chromatid cohesion but is unable to repress transcription at DSBs. We further show that failure to repress transcription at DSBs leads to large-scale genome rearrangements. Cancer samples lacking SA2 display mutational patterns consistent with loss of this pathway. These findings uncover a new function for cohesin that provides insights into its frequent loss in cancer.

Keywords

SA2
STAG2
PBAF
PBRM1
SMARCA4
DNA repair
transcriptional silencing
SWI/SNF
cancer

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